Bipolar disorder is psychiatric disorder characterized by unpredictable swings in mood from mania (or hypomania) to depression. Some patients suffer only from recurrent attacks of mania, which in its pure form is associated with increased psychomotor activity; excessive social extroversion; decreased need for sleep; impulsivity and impairment in judgment; and expansive, grandiose, and sometimes irritable mood. In severe mania, patients may experience delusions and paranoid thinking indistinguishable from schizophrenia. Half of patients with bipolar disorder present with a mixture of psychomotor agitation and activation with dysphoria, anxiety, and irritability. It may be difficult to distinguish mixed mania from agitated depression. In some bipolar patients (bipolar II disorder), the full criteria for mania are lacking, and the requisite recurrent depressions are separated by periods of mild activation and increased energy (hypomania). In cyclothymic disorder, there are numerous hypomanic periods, usually of relatively short duration, alternating with clusters of depressive symptoms that fail, either in severity or duration, to meet the criteria of major depression. The mood fluctuations are chronic and should be present for at least 2 years before the diagnosis is made.
Manic episodes typically emerge over a period of days to weeks, but onset within hours is possible, usually in the early morning hours. An untreated episode of either depression or mania can be as short as several weeks or last as long as 8 to 12 months, and rare patients have an unremitting chronic course. The term rapid cycling is used for patients who have four or more episodes of either depression or mania in a given year. This pattern occurs in 15% of all patients, almost all of whom are women. In some cases, rapid cycling is linked to an underlying thyroid dysfunction and, in others, it is iatrogenically triggered by prolonged antidepressant treatment. Approximately half of patients have sustained difficulties in work performance and psychosocial functioning.
Patients suffering from bipolar disorder typically complain of the following types of symptoms, depending on whether they are in a “manic” or “high” phase versus a “depressed” or “low” phase. In the manic phase symptoms include, but are not limited to (a) increased physical and mental activity and energy (b) heightened mood, exaggerated optimism and self-confidence; (c) excessive irritability, aggressive behavior; (d) decreased need for sleep without experiencing fatigue; (e) grandiose delusions, inflated sense of self-importance; (h) racing speech, racing thoughts, flight of ideas; (i) impulsiveness, poor judgment, distractibility; (j) reckless behavior and In the most severe cases, (k) delusions and hallucinations. In the manic phase symptoms include, but are not limited to (a) prolonged sadness or unexplained crying spells; (b) significant changes in appetite and sleep patterns; (c) irritability, anger, worry, agitation, anxiety; (d) pessimism, indifference; (e) loss of energy, persistent lethargy; (f) feelings of guilt, worthlessness; (g) inability to concentrate, indecisiveness; (h) inability to take pleasure in former interests, social withdrawal; (i) unexplained aches and pains and (j) recurring thoughts of death or suicide.
Bipolar disorder is common, affecting ˜1% of the population in the United States. Onset is typically between 20 and 30 years of age, but many individuals report premorbid symptoms in late childhood or early adolescence. The prevalence is similar for men and women; women are likely to have more depressive and men more manic episodes over a lifetime.
Lithium carbonate is the mainstay of treatment in bipolar disorder, although sodium valproate and olanzapine are equally effective in acute mania, as is lamotrigine in the depressed phase. The response rate to lithium carbonate is 70 to 80% in acute mania, with beneficial effects appearing in 1 to 2 weeks. Lithium also has a prophylactic effect in prevention of recurrent mania and, to a lesser extent, in the prevention of recurrent depression. Serious side effects from lithium administration are rare, but minor complaints such as gastrointestinal discomfort, nausea, diarrhea, polyuria, weight gain, skin eruptions, alopecia, and edema are common.
In the treatment of acute mania, lithium is initiated at 300 mg bid or tid, and the dose is then increased by 300 mg every 2 to 3 days to achieve blood levels of 0.8 to 1.2 meq/L. Because the therapeutic effect of lithium may not appear until after 7 to 10 days of treatment, adjunctive usage of lorazepam (1 to 2 mg every 4 h) or clozepam (0.5 to 1 mg every 4 h) may be beneficial to control agitation. Antipsychotics are indicated in patients with severe agitation who respond only partially to benzodiazepines.
Valproic acid is an alternative in patients who cannot tolerate lithium or respond poorly to it. Valproic acid may be better than lithium for patients who experience rapid cycling (i.e., more than four episodes a year) or who present with a mixed or dysphoric mania. Tremor and weight gain are the most common side effects; hepatotoxicity and pancreatitis are rare toxicities. Carbamazepine and oxcarbazepine, although not formally approved by the U.S. Food and Drug Administration (FDA) for bipolar disorder, have clinical efficacy in the treatment of acute mania. Preliminary evidence also suggests that other anticonvulsant agents such as levtiracetam, zonisamide and topiramate may possess some therapeutic benefit.
The recurrent nature of bipolar mood disorder necessitates maintenance treatment. Compliance is frequently an issue and often requires enlistment and education of concerned family members. Efforts to identify and modify psychosocial factors that may trigger episodes are important, as is an emphasis on lifestyle regularity. Antidepressant medications are sometimes required for the treatment of severe breakthrough depressions, but their use should generally be avoided during maintenance treatment because of the risk of precipitating mania or accelerating the cycle frequency. Loss of efficacy over time may be observed with any of the mood-stabilizing agents. In such situations, an alternative agent or therapy is usually helpful.
There remains a need to provide an effective treatment for mania and/or for bipolar disorder. Preferably, the treatment of bipolar disorder comprises treatment of the depression and the mania. More preferably, the treatment of bipolar disorder comprises treatment of the depression, the mania and the cycling that are characteristic of the disorder.